A great deal of data indicates that orexin (also known as hypocretin) neurons are involved in arousal and narcolepsy. However, we found that that orexin neurons specifically located in lateral hypothalamus (LH) are Fos-activated by cocaine- or morphine-associated stimuli in proportion to the preference that animals express on a conditioned place preference (CPP) test day. Our studies also revealed that chemical stimulation of these cells, or microinfusion of orexin into ventral tegmental area (VTA), reinstates an extinguished drug CPP. Other data from our lab, as well as from other investigators, show that orexin neurotransmission is important for stress-induced reinstatement of drug-self administration, for learning and expressing stimulus-drug relationships, and for glutamate-dependent plasticity in VTA dopamine (DA) neurons. Together, these results provide an important new view on LH orexin projections to midbrain DA neurons, indicating that they play an important role in reward processing and relapse to drug-seeking. The goal of this project is to determine the role of LH orexin neurons and their projections to reward circuitry in the reinstatement of cocaine-seeking following extinction of drug-taking behavior. We will extend our previous CPP studies to the self-administration paradigm and, using anatomical methods, determine if orexin neurons that are activated by cues that induce reinstatement of cocaine-seeking project selectively to one or more areas in reward circuitry. In behavioral experiments with lesions and local microinjections of orexin antagonist, we will also test whether orexin projections from LH to VTA are necessary for cue-induced reinstatment of cocaine-seeking. Finally, using electrophysiological methods, we will examine whether orexin modulates responses of VTA neurons to stimulation of glutamatergic inputs from medial prefrontal cortex. This could reveal mechanisms whereby orexin actions participate in neural plasticity that underlies cueinduced reinstatement of cocaine-seeking. Relevance to public health: Results of these studies will delineate the role of this novel neuropeptide system in cocaine-seeking, and lead to new treatments based upon orexin function that could be effective in maintaining drug abstinence in addicted individuals in the face of cues previously associated with drug taking.